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Glaucoma Opinion IGR 12-4

Neurodegeneration in Glaucoma

Yeni Yücel MD, PhD, FRCPC


The central event in the glaucomatous degenerative process is cell death of retinal ganglion cells (RGCs). It is widely accepted that apoptosis is the way by which RGCs die in glaucoma. In this process, cytoplasm shrinks, specific caspases are activated, DNA fragments, and cells disappear without affecting their neighbours. Using available molecular signatures of apoptosis, a few early studies showed several apoptotic cells in human glaucoma,1 followed by high-pressure animal models in which apoptosis was also detected. These studies fundamentally shifted our perceptions of cell death in glaucoma to apoptotic cell death, considered a hallmark of glaucomatous disease. Does it matter to know whether the RGCs die solely by apoptosis or not? Because cell death by apoptosis is currently being proposed as a key endpoint for clinical trials of future neuroprotective agents in the treatment of glaucoma, it is crucial to evaluate the role of other types of cell death in glaucoma.2 Over the past decade, autophagy has been shown to play a role in neurodegenerative diseases such as in Parkinson's, Alzheimer's, and Huntington's diseases, and deserves exploration in glaucoma.3 Unlike earlier classifications of cell death, the borders between apoptotic cell death type I, autophagic cell death type II and necrotic cell death type III are rather blurry. Let's take for example, autophagic cell death type II. Autophagy, by way of autophagic vacuoles is bulk degradation of mitochondria, organelles and proteins. On one hand, autophagy is important for cell survival processes as seen during caloric restriction and growth factor deprivation, and knockout of implicated molecules leads to neuron loss.4 On the other hand, its excessive activation leads to neuron death in neurodegenerative diseases.5 Recent evidence shows cross talk between autophagy and apoptotic pathways: Beclin-1, a critical molecule in the autophagic pathway, after its caspase-dependent cleavage, contributes to apoptosis.6 Cross talk between autophagy and apoptotic cell death may be injury specific. Although the autophagic pathway is activated in RGCs following optic nerve transection,7 this process is not yet well characterized in glaucoma models. It is likely that altered transport mechanisms in RGCs in experimental glaucoma8 may share common molecular pathways with those implicated in transporting autophagic vacuoles.9 Since the autophagic process is implicated in the alteration of axons and dendrites,5 it may be very relevant to neural degeneration of the visual system in glaucoma. Exploring autophagy in glaucoma may stimulate novel upstream neuroprotective strategies to prevent cell death and prevent blindness.

References

  1. Kerrigan LA, Zack DJ, Quigley HA, Smith SD, Pease ME. TUNEL-positive ganglion cells in human primary open-angle glaucoma. Arch Ophthalmol 1997; 115: 1031-1035.
  2. Guo L, Cordeiro MF. Assessment of neuroprotection in the retina with DARC. Prog Brain Res 2008; 173: 437-450.
  3. Nishiyama J, Miura E, Mizushima N, Watanabe M, Yuzaki M. Aberrant membranes and double-membrane structures accumulate in the axons of Atg5-null Purkinje cells before neuronal death. Autophagy 2007; 3: 591-596.
  4. Marino G, Madeo F, Kroemer G. Autophagy for tissue homeostasis and neuroprotection. CurrOpinCell Biol 2011; DOI: 10.1016/j.ceb.2010.10.001.
  5. Chu CT, Plowey ED, Dagda RK, Hickey RW, Cherra SJ, 3rd, Clark RS. Autophagy in neurite injury and neurodegeneration: in vitro and in vivo models. Methods Enzymol 2009; 453: 217-249.
  6. Djavaheri-Mergny M, Maiuri MC, Kroemer G. Cross talk between apoptosis and autophagy by caspase-mediated cleavage of Beclin 1. Oncogene 2010; 29: 1717-1719.
  7. Kim SH, Munemasa Y, Kwong JM, et al. Activation of autophagy in retinal ganglion cells. J Neurosci Res 2008; 86: 2943-2951.
  8. van Oterendorp C, Lorber B, Jovanovic Z, Yeo G, Lagreze WA, Martin KR. The expression of dynein light chain DYNLL1 (LC8-1) is persistently downregulated in glaucomatous rat retinal ganglion cells. Exp Eye Res 2011; DOI:10.1016/j.exer.2010.11.013.
  9. Batlevi Y, Martin DN, Pandey UB, et al. Dynein light chain 1 is required for autophagy, protein clearance, and cell death in Drosophila. Proc Natl Acad Sci USA 2010; 107: 742-747.

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